In 1990, Gunasekera and co-workers at the Harbor Branch Oceanographic Institute reported the isolation of (+)-discodermolide (1), an architecturally novel metabolite of the marine sponge Discodermia dissoluta (0.002% w/w). (See, Gunasekera, et al., J. Org. Chem. 1990, 55, 4912. Correction: J. Org. Chem. 1991, 56, 1346).

Initial studies revealed that (+)-discodermolide suppresses both the two-way mixed-lymphocyte reaction and the concanavalin A-induced mitogenesis of murine splenocytes in vitro with no associated cytotoxicity. Moreover, (+)-1 suppresses the in vivo graft-vs.-host splenomegaly response induced by injection of parental splenocytes into F1 recipient mice, with potency intermediate between those of cyclosporin A and FK506. (Longley, et al., Transplantation 1991, 52, 650; Longley, et al., Transplantation 1991, 52, 656; Longley, et al. Ann. N.Y. Acad. Sci. 1993, 696, 94). These findings stimulated the recent discovery that (+)-1 arrests cell development at the M phase by binding and stabilizing mitotic spindle microtubules; thus discodermolide resembles taxol in its mode of action, but the microtubule binding affinity of 1 is much higher. (ter Haar, et al., Biochemistry 1996, 35, 243; Hung, et al., Chemi. & Biol. 1996, 3, 287). These and other results suggest that (+)-discodermolide holds considerable promise as an anticancer agent. Due to the scarcity of natural material, complete evaluation of its biological profile has depended almost wholly on (+)-discodermolide's synthetic preparation.
The absolute configuration of discodermolide remained undefined until Schreiber et al. synthesized both antipodes of 1. (Nerenberg, et al. J. Am. Chem. Soc. 1993, 115, 12621; Hung, et al., Chem. & Biol. 1994, 1, 67). Interestingly, the unnatural (−) antipode also displays significant immunosuppressant activity.
One of the key structural features of discodermolide its Δ8,9-olefinic bond. cis-Selectivity at the Δ8,9-double bond in discodermolide compounds or analogs thereof is highly desirable for chemical or biological activity of these molecules. Martello, L. A., et al., Chem. Biol., 2001, 120, 1. In approaching the synthesis of discodermolide compounds, Smith, et al. (U.S. Pat. No. 6,242,616 B1) employed Wittig chemistry to provide the eventual Δ8,9-double bond of certain discodermolide intermediate compounds bearing an acid labile hydroxyl protecting group at C-11. Under certain reaction conditions using phosphonium salt intermediates with bulky trialkylsilyl acid labile C-11 hydroxyl protecting groups, the reaction provided cis/trans ratios of about 20 at the Δ8,9-double bond in good yield. Unfortunately, preparation of the desired Wittig precursor phosphonium salts to discodermolide compounds having these specified C-11 protecting groups has the drawback of requiring the use of very high pressure (as great as 12 kbar or above). Reaction rates in some instances are very slow and, as such, the reactions require extended reaction times (as long as 10-14 days). Use of these very high pressure process conditions has the further drawback of requiring specialized reactors and handling equipment. In the absence of these extreme pressure conditions, undesirable amounts of cyclized by-products are formed (Scheme 1). Attempted formation of certain phosphonium salts under more convenient ambient pressure conditions led to HI-catalyzed decomposition and increased levels of cyclized by-products. Smith, et al., Org. Lett. (2003), 5(23), 4405-4408.

There is therefore a need for improved synthetic methods which provide high yield and high selectivity, and at a relatively high rate of reaction, using better, more convenient and/or less expensive process methodology than many processes known heretofore for the preparation of polyhydroxy, dienyl lactones such as the discodermolides and their synthetic intermediates, as well as a need for compounds having similar chemical and/or biological activity. The present invention is directed to these and other important ends.